Novel TGF Beta modulator in Osteoarthritis

Background:
Osteoarthritis (OA) is a painful and disabling condition of the joints affecting millions of people. Ageing is the primary risk factor, but how ageing results in OA is still an enigma. OA is characterized by degeneration of the articular cartilage, which has a very limited reparative capacity. Therefore, detection of early and minimum tissue damage is essential to stop the progression of the disease. However, diagnostic tools have low sensitivity and specificity and currently, there is no cure for OA.

Technology Overview:
To find novel druggable targets that modulate the pathological TGFβ signaling pathway in OA, researchers at the LUMC analyzed secreted TGF-β/BMP signaling modulators that are not essential for signaling but can potentiate or inhibit TGF-β/BMP signaling in cell/tissue-type and dynamic manner. They examined this in two OA mouse models that develop spontaneous OA during ageing, and in an inducible model, in which the medial meniscus is destabilized (DMM). Among others, they found a novel candidate that had not been linked previously to OA. They found that this novel modulator was expressed in mouse and human OA samples. In addition, they observed a correlation between its expression and the disease severity (Mankin score) in human specimens.

Figure 1: Immunohistochemistry analysis of human OA samples using a specific antibody against TGF modulator. Samples were scored for the expression of specific staining in chondrocytes of different areas of the cartilage and correlated to the severity (Mankin score).
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Preliminary in vitro experiments point out towards an involvement of this TGFβ modulator in chondrogenic differentiation processes. The scientists have found that its endogenous expression (mRNA and protein) was increased during differentiation of ATDC5 cells under chondrogenic conditions. Modulation of its expression (overexpression or knock-down) interfered with the terminal differentiation by respectively, increasing or inhibiting this process. Therefore, targeting such TGFβ modulator appears to be an intriguing option to foster TGFβ towards its anabolic profile, ceasing OA-progression.

Figure 2: Modulation of the expression of the TGF modulator alters terminal differentiation of ATDC5 cells. ATDC5 stable cells with knockdown expression or overexpressing the candidate gene were seeded in micromass and hypertrophic differentiation was assessed by alizarin red staining. RNA was isolated from these cells and the relative gene expression versus GAPDH is shown in the graphs.

Key benefits

Because of the lack of a cure and specific biomarkers for OA, these findings point towards a possible solution in these areas.

Applications

Possible diagnostic marker, possible therapeutic target.

Development stage

Seeking co-development partners to further develop diagnostic assays and to validate the target in an in vivo setting.